Antibiotics Before Checkpoint Inhibitors Tied to Worse Survival

SAN FRANCISCO — Use of broad-spectrum antibiotics 30 days before starting an immune checkpoint inhibitor was associated with a dramatic reduction in cancer patients’ survival, a prospective study found.

In the analysis of 196 patients, 84% of whom had metastatic disease, median survival was just 2 months in patients who had received a prior antibiotic compared with 26 months for those who had not (P<0.001), David Pinato, MD, PhD, of Imperial College in London, reported here.

“We know that part of the efficacy of immune checkpoint inhibitors strongly relies on the influence of the microbiome,” Pinato said during his presentation at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. “We also know that broad spectrum antibiotics can completely abrogate microbial diversity and induce protracted gut dysbiosis.”

Most of the patients in the study had non-small cell lung cancer (NSCLC; 60%) or melanoma (20%), but the study also included patients with renal cell carcinoma and other forms of cancer.

“Signals for worse overall survival were preserved irrespective of tumor site,” Pinato noted.

Indeed, median survival was consistently worse across all three groups in patients with versus without prior antibiotic use:

• NSCLC: 2.5 vs 26 months (P<0.001)
• Melanoma: 3.9 vs 14 months (P<0.001)
• Other cancers: 1.1 vs 11 months (P<0.001)

For the study, Pinato’s group analyzed a data set of patients treated with immune checkpoint inhibitors in two academic centers in London from 2015 to 2018. Virtually all patients were treated with anti-PD-1/PD-L1 monotherapy, and seven with an anti-PD-1/CTLA-4 combination. The main outcome was overall survival from the time of treatment initiation until death.

“We qualified prior antibiotic exposure using a time frame of 30 days from the first day of immune checkpoint inhibitor treatment as well as concurrent antibiotic treatment from cycle one, day one, until cessation,” Pinato explained.

The same detrimental effect was not observed among patients who took antibiotics concurrently with immunotherapy (P=0.65). He noted that the absence of an effect from concurrent antibiotic treatment on response and survival suggested that the timing of antibiotic exposure is crucial and that it is safe to use concurrent antibiotic treatment in patients treated with immunotherapy.

In analyzing the relationship between prior antibiotic exposure and radiologic response to treatment, investigators also observed a significantly higher proportion of patients who had progressive disease as their best response to treatment compared with the antibiotic-naive group (81% with vs 44% without, respectively).

The most frequently prescribed antibiotics were beta lactams, which were given mostly for less than 7 days and as a single course of therapy. There was no association between survival odds and the type of antibiotic used, nor was there any association with corticosteroid use.

“These data are showing an independent detrimental effect, both on response and survival, in selected patients treated with immune checkpoint inhibitors in routine clinical practice,” Pinato said.

Discussant Jason Luke, MD, of the University of Chicago, said it was “quite amazing” that the microbiome could make this much of a difference to patient outcomes.

Luke and colleagues at the University of Chicago are starting to look at supplementation of a pharmaceutical grade probiotic to see if they can augment or rescue response to checkpoint inhibitor therapy.

“The fecal microbiome may be both a predictive biomarker as well as a therapeutic target for managing checkpoint inhibitor efficacy and toxicity,” he said.